Amyotrophic Lateral Sclerosis (ALS) and related motor neuron diseases are among the cruelest of human illnesses; patients cannot move or speak, but their minds are preserved until the end. Unfortunately, the basic mechanisms leading to dysfunction and death of motor neurons are poorly understood. Recent clinical-pathological studies suggest that neurofilamentous swelling occur in proximal motor axons early in the course of ALS, and it has been suggested that this neurofibrillary axonal pathology results from abnormalities in the biology of the neuronal cytoskeleton. The major slowly-transported constituents of the cytoskeleton have recently been identified, and it is now possible to ask specific questions concerning the mechanisms leading to cytoskeletal pathology in nerve cells. We have advanced the hypothesis that some of these disorders are the result of abnormalities in the synthesis/transport/organization/degradation of neurofilaments, one of the major components of the cytoskeleton. We plan to investigate four models in which there is pre-existent evidence indicating an abnormality in the biology of neurofilaments: Hereditary Canine Spinal Muscular Atrophy (HCSMA), a unique animal model of motor neuron disease which shows features in common with ALS; aluminum chloride intoxication; regeneration after nerve trauma; and, acrylamide neuropathy. Each of these disorders shows alterations in the pattern of distribution of neurofilaments, but the location of this cytoskeletal change differs in the four models. Study of the structural changes in motor neurons in these models will be of value in clarifying the ways in which normal neurons maintain their cytoskeleton and how alterations in the biology of neurofilaments is affected in disease processes. We believe that this research will be of great value in understanding some of the functional abnormalities associated with cytoskeletal pathology in human neurologic disease.